As the primary excitatory neurotransmitter in the mammalian central nervous system, glutamate mediates signaling between neurons by activating at least five different types of membrane bound receptors. Characterizing these receptors is a top priority not only because of their function in normal processes such as learning and memory, but also due to their role in causing damage in pathological states such as ischemia, stroke, epilepsy, and Alzheimer's disease. The general goals of this project are to provide a better understanding of the molecular interactions that control these processes, and to obtain new evidence on the structures of the receptors themselves. Continuing structure-activity studies of "rigidified" glutamate analogues are intended to further our knowledge of receptor binding site preferences. In addition, new models of the three-dimension structures of several of the receptors are to be tested with proposed photoaffinity probes and de novo designed ligands. The ultimate goal is a complete understanding at the molecular level of agonist and antagonist action at each receptor type, which could ultimately lead to the improved design of CNS drugs.